Tag: Chronic Lymphocytic Leukemia

Fixed-Duration vs Continuous Targeted Therapy in Frontline CLL: Insights from the Phase III CLL17 Trial

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SUMMARY: The American Cancer Society estimates that for 2026, about 22,760 new cases of Chronic Lymphocytic Leukemia (CLL) will be diagnosed in the US and 4350 patients will die of the disease. CLL accounts for about one-quarter of the new cases of leukemia. The average age of patients diagnosed with CLL is around 70 years, and is rarely seen in people under age 40, and is extremely rare in children.

Evolving Treatment Paradigms in CLL            

The therapeutic landscape of CLL has undergone a profound transformation over the past decade, moving away from chemoimmunotherapy toward mechanism-based targeted agents. Brutons Tyrosine Kinase (BTK) inhibitors and the BCL2 inhibitor Venetoclax (VENCLEXTA®) have become foundational therapies, delivering durable disease control across biologic risk groups. Historically, BTK inhibitors were administered continuously until progression or intolerance, whereas Venetoclax-based combinations introduced the possibility of time-limited treatment.

The rationale for fixed-duration therapy stems from the observation that rational combinations can induce deeper remissions, including undetectable Minimal Residual Disease (MRD), potentially allowing for treatment-free intervals and reduced cumulative toxicity. While Venetoclax–Rituximab in relapsed disease and Venetoclax–Obinutuzumab in the frontline setting validated this concept, the relative efficacy of fixed-duration regimens compared with continuous BTK inhibition remained an unanswered question, until now.

Trial Design and Patient Population

CLL17 is an international, investigator-initiated, Phase III randomized trial designed to directly compare fixed-duration and continuous targeted treatment strategies, in previously untreated CLL patients. A total of 909 treatment-naïve patients were enrolled across 174 centers in 13 countries and randomly assigned in a 1:1:1 ratio to receive:

Fixed-duration Venetoclax plus Obinutuzumab (N=303)

Fixed-duration Venetoclax plus Ibrutinib (N=305)

Continuous Ibrutinib monotherapy (N=301)

Randomization was stratified by fitness status, IGHV mutation status, and the presence of del(17p) and/or TP53 mutation. The study population reflected real-world heterogeneity, with a median age of 66 years, 44% classified as unfit (based on CIRS scores greater than 6, a creatinine clearance of less than 70 ml per minute, or both), more than half harboring unmutated IGHV, 7.6% of the patients with del(17p) or TP53 mutation (or both), and nearly 20% exhibiting complex karyotypes. High- and very high-risk disease by the CLL International Prognostic Index was present in more than 60% of patients, underscoring the clinical relevance of the cohort. The Primary endpoint was investigator-assessed Progression-Free Survival (PFS), with the trial powered to test the noninferiority of each fixed-duration regimen versus continuous Ibrutinib. Key Secondary endpoints included Overall Survival (OS), MRD negativity, Response Rates, and Safety.

Efficacy Outcomes: Noninferiority Achieved

At a median follow-up of 34.2 months, in this prespecified interim analysis, both fixed-duration strategies met the prespecified criteria for noninferiority compared with continuous Ibrutinib. Three-year PFS rates were remarkably similar across treatment arms:

81.1% with Venetoclax–Obinutuzumab

79.4% with Venetoclax–Ibrutinib

81.0% with continuous Ibrutinib

Hazard ratios for progression or death favored neither continuous nor fixed-duration therapy, providing the first prospective evidence that time-limited targeted regimens can match the disease control achieved with indefinite BTK inhibition in the frontline setting.

Overall Survival at three years exceeded 90% in all groups, with no meaningful differences observed at this interim analysis. Longer follow-up will be required to determine whether survival curves diverge with time, particularly in biologically high-risk subgroups.

Depth of Remission and MRD Dynamics

Marked differences emerged in depth of response. Undetectable MRD in peripheral blood at the end of treatment was achieved in:

73.3% of patients treated with Venetoclax–Obinutuzumab

47.2% of those receiving Venetoclax–Ibrutinib

0% of patients on continuous Ibrutinib

These findings reinforce the well-established limitation of single-agent BTK inhibition in achieving deep molecular remissions and highlight a key advantage of Venetoclax-based combinations. While end-of-treatment MRD has been associated with long-term outcomes in fixed-duration regimens, its prognostic value relative to continuous BTK inhibition remains less clear. Ongoing longitudinal MRD assessments in CLL17 may help clarify whether differences in MRD depth ultimately translate into durable clinical benefit.

Safety and Tolerability Considerations

Adverse events were common across all treatment arms, reflecting the immunocompromised nature of the CLL population. Infections affected nearly 80% of patients overall, with serious and fatal infections occurring more frequently in the Venetoclax–Obinutuzumab arm. Importantly, trial enrollment coincided with the COVID-19 pandemic, and approximately 10% of patients experienced severe COVID-19–related infections.

Cytopenias, particularly neutropenia, were more frequent with combination regimens, especially Venetoclax–Obinutuzumab. However, these events were largely confined to the first year of therapy and resolved after treatment completion. In contrast, cardiac toxicities, including atrial fibrillation and hypertension, were more commonly associated with Ibrutinib-containing regimens, consistent with prior experience.

Tumor lysis syndrome was infrequent (<5%) across Venetoclax-containing arms, demonstrating that standard ramp-up strategies and debulking approaches effectively mitigate this risk, even in older and unfit patients.

Subgroup Insights and Clinical Implications

Fixed-duration therapy performed well across most biologic subgroups. Notably, patients with unmutated IGHV did not experience inferior outcomes with time-limited treatment compared with continuous Ibrutinib, supporting broader use of fixed-duration strategies. Patients with mutated IGHV achieved particularly favorable outcomes with Venetoclax–Obinutuzumab, consistent with the more indolent biology of this subgroup.

For patients with del(17p) or TP53 mutations, outcomes were encouraging with BTK inhibitor–containing regimens, although the small sample size and limited follow-up preclude definitive conclusions. Continuous therapy did not clearly outperform fixed-duration Venetoclax–Ibrutinib in this population, highlighting the need for ongoing observation and biomarker-driven analyses.

Positioning CLL17 in the Current Treatment Landscape

The results of CLL17 complement and extend findings from earlier studies such as CLL13, CLL14, CAPTIVATE, and GLOW, while providing the first direct, randomized comparison between fixed-duration and continuous targeted therapy. Importantly, the trial was conducted during the emergence of next-generation BTK inhibitors with improved cardiac safety profiles, suggesting that the central question addressed by CLL17, time-limited versus continuous therapy, will remain clinically relevant regardless of the specific BTK inhibitor chosen.

Conclusions

The first analysis of the Phase III CLL17 trial demonstrates that fixed-duration Venetoclax–Obinutuzumab and Venetoclax–Ibrutinib are noninferior to continuous Ibrutinib in previously untreated CLL, with comparable Progression-Free Survival and excellent Overall Survival. These findings provide high-level evidence supporting fixed-duration therapy as a viable frontline strategy for most patients, offering the advantages of treatment-free intervals and deep remissions without compromising efficacy. As follow-up matures, CLL17 will further inform patient selection, remission durability, and the long-term significance of MRD. For now, the trial marks a pivotal step toward more personalized, time-limited treatment strategies in CLL.

Fixed-Duration versus Continuous Treatment for Chronic Lymphocytic Leukemia. Al-Sawaf O, Stumpf J,  Zhang C, et al. for the CLL17 Trial Investigators. N Engl J Med 2026;394:1084-1096.

FDA Approves CALQUENCE® with VENCLEXTA® for Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

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SUMMARY: The FDA on February 19, 2026, approved Acalabrutinib (CALQUENCE®) in combination with Venetoclax (VENCLEXTA®) for adults with Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL).

The American Cancer Society estimates that for 2026, about 22,760 new cases of Chronic Lymphocytic Leukemia (CLL) will be diagnosed in the US and 4350 patients will die of the disease. CLL accounts for about one-quarter of the new cases of leukemia. The average age of patients diagnosed with CLL is around 70 years, and CLL is rarely seen in people under age 40, and is extremely rare in children. Patients with CLL often receive continuous therapy with either Brutons Tyrosine Kinase (BTK) inhibitor, time limited therapy with BCL2 inhibitor Venetoclax given along with anti-CD20 antibody Obinutuzumab (GAZYVA®), or under certain circumstances, chemoimmunotherapy.

Brutons Tyrosine Kinase (BTK) is a member of the Tec family of kinases, downstream of the B-cell receptor, and is predominantly expressed in B-cells. It is a mediator of B-cell receptor signaling in normal and transformed B-cells. BTK inhibitors inhibit cell proliferation and promote programmed cell death (Apoptosis) by blocking B-cell activation and signaling. BTK is a validated molecular target found across numerous B-cell leukemias and lymphomas including CLL, Mantle Cell Lymphoma (MCL), and Waldenstrom Macroglobulinemia (WM). Four BTK inhibitors are presently approved by the FDA. They include first generation Ibrutinib (IMBRUVICA®) and second generation agents such as Acalabrutinib (CALQUENCE®), Zanubrutinib (BRUKINSA®) and non-covalent BTKi, Pirtobrutinib (JAYPIRCA®).

The pro-survival (anti-apoptotic) protein BCL2 is over expressed by CLL cells and regulates clonal selection and cell survival. Venetoclax is a second generation, oral, selective, small molecule inhibitor of BCL2 and restores the apoptotic processes in tumor cells. Venetoclax is frequently combined with the infusion-based drug Obinutuzumab, which can impose a logistical burden on patients. The combination of Acalabrutinib plus Venetoclax, were noted to be synergistic.

The AMPLIFY trial is a randomized, global, multi-center, open-label Phase III study designed to assess the efficacy and safety of Acalabrutinib in combination with Venetoclax, with or without Obinutuzumab, compared to investigators choice of standard chemoimmunotherapy. In this study, 867 patients (N=867) across 171 locations worldwide with previously untreated CLL were randomized 1:1:1 to receive a fixed-duration regimen of Acalabrutinib and Venetoclax with Obinutuzumab (AVO; N=286), Acalabrutinib and Venetoclax without Obinutuzumab (AV; N=291), or Standard-of-Care chemoimmunotherapy with either Fludarabine plus Cyclophosphamide and Rituximab (FCR) or Bendamustine plus Rituximab (BR) (FCR/BR; N=290). The median patient age was 61 years, 64.5% were male, and 58.6% had CLL with unmutated IGHV. Eligible patients had an ECOG performance status of 0 to 2 and active disease, requiring treatment as per the International Workshop on CLL 2018 criteria. Patients with prior CLL-specific treatments, 17p deletions, TP53 mutations, transformation of CLL to aggressive Non-Hodgkin Lymphoma, Central Nervous System involvement, or a history of Progressive Multifocal Leukoencephalopathy were excluded. The Primary endpoint of the trial was Progression Free Survival (PFS) as assessed by an Independent Review Committee (IRC). Key Secondary endpoints included PFS assessed by investigators, undetectable Minimal Residual Disease (uMRD; 10-4 cutoff) rate assessed in peripheral blood in the treatment groups, Overall Survival (OS), Overall Response Rate (ORR), Duration of Response, and Time to next treatment.

Efficacy Outcomes (Median Follow-Up: 41 Months)

Progression-Free Survival (PFS) — BICR Assessed

  • AVO vs FCR/BR
    • HR: 0.42
    • P < 0.0001
    • 58% reduction in risk of progression or death
  • AV vs FCR/BR
    • HR: 0.65
    • P = 0.0038
    • 35% reduction in risk of progression or death
  • 36-Month PFS Rates
    • AVO: 83%
    • AV: 76.8%
    • FCR/BR: 66.5%
  • Median PFS
    • AVO: Not reached
    • AV: Not reached
    • FCR/BR: 47.6 months

Overall Response Rate (ORR) — BICR Assessed

  • AVO: 92.7%
  • AV: 92.8%
  • FCR/BR: 75.2%
  • P < 0.0001 for both AVO vs FCR/BR and AV vs FCR/BR

Overall Survival (OS)

  • AV vs FCR/BR
    • HR: 0.33
    • P < 0.0001
    • Demonstrated a strong trend toward improved Overall Survival

Serious Adverse Events occurred in 38.4% (AVO group), 24.7% of patients (AV group), and 27.4% (FCR/BR group). Grade 3 or more neutropenia among the treatment groups, was noted in 35.2%, 26.8% and 32.4%, respectively. COVID-19-related deaths affected 25 patients in the AVO group, 10 patients in the AV group, and 21 patients in the FCR/BR group.

Conclusion

The AMPLIFY study met its Primary endpoint, demonstrating superior Progression-Free Survival (PFS) with both AVO and AV compared with standard chemoimmunotherapy.

Key Takeaways

  • Both combinations produced deep and durable responses
  • Represent a more effective, fixed-duration treatment strategy
  • Offer a shift away from traditional chemoimmunotherapy

Clinical Distinction Between Regimens

AV (Acalabrutinib + Venetoclax):

  • First all-oral, fixed-duration regimen
  • Designed for fit, treatment-naïve CLL patients
  • Provides meaningful convenience
  • Demonstrates a manageable safety profile

AVO (Acalabrutinib + Venetoclax + Obinutuzumab):

  • Further improved efficacy outcomes
  • Associated with:
    • Higher rates of serious adverse events
    • Increased COVID-19–related deaths

 

Fixed-Duration Acalabrutinib Combinations in Untreated Chronic Lymphocytic Leukemia. Brown JR, Seymour JF, Wojciech Jurczak, et al. for the AMPLIFY investigators. N Engl J Med 2025;392:748-762

JAYPIRCA® versus IMBRUVICA® in Treatment Naïve CLL/SLL: Insights from the Phase III BRUIN CLL-314 Trial

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SUMMARY: The American Cancer Society estimates that for 2026, about 22,760 new cases of Chronic Lymphocytic Leukemia (CLL) will be diagnosed in the US and 4350 patients will die of the disease. CLL accounts for about one-quarter of the new cases of leukemia. The average age of patients diagnosed with CLL is around 70 years, and is rarely seen in people under age 40, and is extremely rare in children.

Progress and Persistent Gaps with Covalent BTK Inhibitors

The advent of covalent Bruton Tyrosine Kinase inhibitors (cBTKi), Ibrutinib (IMBRUVICA®), Acalabrutinib (CALQUENCE®), and Zanubrutinib (BRUKINSA®), has fundamentally altered the treatment paradigm for Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL). These agents have demonstrated robust activity across both treatment-naïve (TN) and relapsed/refractory (R/R) settings, establishing BTK inhibition as a cornerstone of therapy.

Despite these advances, cBTKi share inherent pharmacologic and clinical limitations. Short half-lives, variable oral bioavailability, and off-target kinase inhibition can lead to incomplete target suppression, cumulative toxicity, treatment interruptions, and ultimately compromised long-term efficacy. While second-generation agents such as Acalabrutinib and Zanubrutinib were developed to improve selectivity and tolerability, their benefits over Ibrutinib have been demonstrated primarily in the R/R setting, and direct comparisons in the treatment-naïve population have been lacking.

Rationale for Noncovalent BTK Inhibition

Pirtobrutinib (JAYPIRCA®) represents a mechanistically distinct approach to BTK inhibition. As a highly selective, noncovalent BTK inhibitor (ncBTKi), it binds independently of the C481 residue, enabling sustained target inhibition even in the presence of common resistance mutations. Its low nanomolar potency and pharmacokinetic profile allow for continuous BTK suppression throughout the dosing interval, raising the possibility of enhanced efficacy with improved tolerability relative to cBTKi.

BRUIN CLL-314: Trial Design and Objectives

BRUIN CLL-314 (LOXO-BTK-20030) is a global, randomized, open-label Phase III study and, to date, the first trial to directly compare a noncovalent BTK inhibitor with a covalent BTK inhibitor in CLL/SLL. The study enrolled 662 BTKi-naïve patients across 23 countries, including both treatment-naïve patients and those with R/R disease.

Participants were randomized 1:1 to receive Pirtobrutinib (200 mg once daily) or Ibrutinib (420 mg once daily), administered continuously until disease progression or unacceptable toxicity. Stratification factors included del(17p) status and number of prior lines of therapy. The Primary endpoint was Independent Review Committee (IRC)–assessed Overall Response Rate (ORR) in the Intention-to-Treat (ITT) population and in patients with R/R disease. Progression-Free Survival (PFS) was a key Secondary endpoint.

Patient Population

Baseline characteristics were well balanced between treatment arms. The median age was 67 years, approximately two-thirds of patients were male, and over half were enrolled from Europe. High-risk molecular features, including del(17p), unmutated IGHV, and complex karyotype, were evenly distributed. Among patients with R/R disease, the median number of prior therapies was one.

Efficacy Outcomes: ORR and Early PFS Signals

The study met its primary objective, demonstrating statistically significant noninferiority of Pirtobrutinib compared with Ibrutinib for IRC-assessed ORR.

  • Intent to Treat population: ORR was 87.0% with Pirtobrutinib versus 78.5% with Ibrutinib
  • Treatment-Naïve patients: ORR was 92.9% versus 85.8%, respectively
  • Relapsed/Refractory patients: ORR was 84.0% versus 74.8%, respectively

Notably, response rates consistently favored Pirtobrutinib across clinically relevant high-risk subgroups, including patients with del(17p), unmutated IGHV, and complex karyotype.

While PFS data remain immature, early descriptive analyses revealed a favorable trend for Pirtobrutinib. Investigator-assessed PFS suggested a reduction in the risk of progression or death across the ITT, Relapsed/Refractory, and treatment-naïve populations, with the most pronounced benefit observed in treatment-naïve patients, the subgroup with the longest follow-up to date.

Safety and Tolerability

Pirtobrutinib demonstrated a favorable safety profile compared with Ibrutinib. Rates of cardiac adverse events, including atrial fibrillation/flutter and hypertension, were lower with Pirtobrutinib, consistent with its higher selectivity for BTK and reduced off-target kinase inhibition.

Patient-reported outcomes further supported improved tolerability, with lower rates of symptomatic adverse events such as myalgia, bruising, headache, diarrhea, and cough. These findings are particularly relevant in CLL/SLL, where long-term therapy places a premium on safety, adherence, and quality of life.

Clinical Implications and Sequencing Considerations

The results of BRUIN CLL-314 carry important implications for clinical practice. Historically, noncovalent BTK inhibitors were positioned primarily as salvage therapy following cBTKi resistance. These data challenge that paradigm by demonstrating robust activity, favorable tolerability, and early PFS benefit for Pirtobrutinib in BTKi-naïve patients, including those treated in the frontline setting.

The pronounced benefit observed in treatment-naïve patients is especially noteworthy, as this represents the first randomized Phase III evidence directly comparing BTK inhibitors head to head in this population. For patients requiring long-term continuous therapy, improved tolerability may translate into prolonged disease control and better overall outcomes.

Sequencing remains an evolving consideration. Venetoclax-based fixed-duration regimens continue to provide an effective option following BTK inhibition, and prior studies suggest preserved activity of Venetoclax after Pirtobrutinib. For older patients or those anticipated to require limited lines of therapy, initial treatment choice may reasonably prioritize safety, convenience, and durability of response.

Study Limitations

Key limitations include the open-label design and relatively short follow-up for PFS. However, the use of a blinded IRC for response assessment and minimal imbalance in early treatment discontinuation mitigate concerns regarding bias. Ongoing follow-up and prespecified analyses will further clarify the long-term impact of Pirtobrutinib on disease control and survival outcomes.

Conclusion

BRUIN CLL-314 establishes Pirtobrutinib as a compelling next-generation BTK inhibitor, demonstrating noninferior, and numerically superior response rates compared with Ibrutinib, alongside early signals of improved Progression-Free Survival and a more favorable safety profile. These findings support the potential role of Pirtobrutinib not only after cBTKi failure but also in earlier lines of therapy, including the frontline setting, where durable efficacy and tolerability are paramount.

Pirtobrutinib Versus Ibrutinib in Treatment-Naïve and Relapsed/Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma. Woyach JA, Qiu L, Grosicki S, et al. J Clin Oncol. DOI: 10.1200/JCO-25-02477

Fixed-Duration vs Continuous Targeted Therapy in Frontline CLL: Insights from the Phase III CLL17 Trial

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SUMMARY: The American Cancer Society estimates that for 2026, about 22,760 new cases of Chronic Lymphocytic Leukemia (CLL) will be diagnosed in the US and 4350 patients will die of the disease. CLL accounts for about one-quarter of the new cases of leukemia. The average age of patients diagnosed with CLL is around 70 years, and is rarely seen in people under age 40, and is extremely rare in children.

Evolving Treatment Paradigms in CLL            

The therapeutic landscape of CLL has undergone a profound transformation over the past decade, moving away from chemoimmunotherapy toward mechanism-based targeted agents. Brutons Tyrosine Kinase (BTK) inhibitors and the BCL2 inhibitor Venetoclax have become foundational therapies, delivering durable disease control across biologic risk groups. Historically, BTK inhibitors were administered continuously until progression or intolerance, whereas Venetoclax-based combinations introduced the possibility of time-limited treatment.

The rationale for fixed-duration therapy stems from the observation that rational combinations can induce deeper remissions, including undetectable Minimal Residual Disease (MRD), potentially allowing for treatment-free intervals and reduced cumulative toxicity. While Venetoclax–Rituximab in relapsed disease and Venetoclax–Obinutuzumab in the frontline setting validated this concept, the relative efficacy of fixed-duration regimens compared with continuous BTK inhibition remained an unanswered question, until now.

Trial Design and Patient Population

CLL17 is an international, investigator-initiated, Phase III randomized trial designed to directly compare fixed-duration and continuous targeted treatment strategies, in previously untreated CLL patients. A total of 909 treatment-naïve patients were enrolled across 174 centers in 13 countries and randomly assigned in a 1:1:1 ratio to receive:

Fixed-duration Venetoclax plus Obinutuzumab (N=303)

Fixed-duration Venetoclax plus Ibrutinib (N=305)

Continuous Ibrutinib monotherapy (N=301)

Randomization was stratified by fitness status, IGHV mutation status, and the presence of del(17p) and/or TP53 mutation. The study population reflected real-world heterogeneity, with a median age of 66 years, 44% classified as unfit (based on CIRS scores greater than 6, a creatinine clearance of less than 70 ml per minute, or both), more than half harboring unmutated IGHV, 7.6% of the patients with del(17p) or TP53 mutation (or both), and nearly 20% exhibiting complex karyotypes. High- and very high-risk disease by the CLL International Prognostic Index was present in more than 60% of patients, underscoring the clinical relevance of the cohort. The Primary endpoint was investigator-assessed Progression-Free Survival (PFS), with the trial powered to test the noninferiority of each fixed-duration regimen versus continuous Ibrutinib. Key Secondary endpoints included Overall Survival (OS), MRD negativity, Response Rates, and Safety.

Efficacy Outcomes: Noninferiority Achieved

At a median follow-up of 34.2 months, in this prespecified interim analysis, both fixed-duration strategies met the prespecified criteria for noninferiority compared with continuous Ibrutinib. Three-year PFS rates were remarkably similar across treatment arms:

81.1% with Venetoclax–Obinutuzumab

79.4% with Venetoclax–Ibrutinib

81.0% with continuous Ibrutinib

Hazard ratios for progression or death favored neither continuous nor fixed-duration therapy, providing the first prospective evidence that time-limited targeted regimens can match the disease control achieved with indefinite BTK inhibition in the frontline setting.

Overall Survival at three years exceeded 90% in all groups, with no meaningful differences observed at this interim analysis. Longer follow-up will be required to determine whether survival curves diverge with time, particularly in biologically high-risk subgroups.

Depth of Remission and MRD Dynamics

Marked differences emerged in depth of response. Undetectable MRD in peripheral blood at the end of treatment was achieved in:

73.3% of patients treated with Venetoclax–Obinutuzumab

47.2% of those receiving Venetoclax–Ibrutinib

0% of patients on continuous Ibrutinib

These findings reinforce the well-established limitation of single-agent BTK inhibition in achieving deep molecular remissions and highlight a key advantage of Venetoclax-based combinations. While end-of-treatment MRD has been associated with long-term outcomes in fixed-duration regimens, its prognostic value relative to continuous BTK inhibition remains less clear. Ongoing longitudinal MRD assessments in CLL17 may help clarify whether differences in MRD depth ultimately translate into durable clinical benefit.

Safety and Tolerability Considerations

Adverse events were common across all treatment arms, reflecting the immunocompromised nature of the CLL population. Infections affected nearly 80% of patients overall, with serious and fatal infections occurring more frequently in the Venetoclax–Obinutuzumab arm. Importantly, trial enrollment coincided with the COVID-19 pandemic, and approximately 10% of patients experienced severe COVID-19–related infections.

Cytopenias, particularly neutropenia, were more frequent with combination regimens, especially Venetoclax–Obinutuzumab. However, these events were largely confined to the first year of therapy and resolved after treatment completion. In contrast, cardiac toxicities, including atrial fibrillation and hypertension, were more commonly associated with Ibrutinib-containing regimens, consistent with prior experience.

Tumor lysis syndrome was infrequent (<5%) across Venetoclax-containing arms, demonstrating that standard ramp-up strategies and debulking approaches effectively mitigate this risk, even in older and unfit patients.

Subgroup Insights and Clinical Implications

Fixed-duration therapy performed well across most biologic subgroups. Notably, patients with unmutated IGHV did not experience inferior outcomes with time-limited treatment compared with continuous Ibrutinib, supporting broader use of fixed-duration strategies. Patients with mutated IGHV achieved particularly favorable outcomes with Venetoclax–Obinutuzumab, consistent with the more indolent biology of this subgroup.

For patients with del(17p) or TP53 mutations, outcomes were encouraging with BTK inhibitor–containing regimens, although the small sample size and limited follow-up preclude definitive conclusions. Continuous therapy did not clearly outperform fixed-duration Venetoclax–Ibrutinib in this population, highlighting the need for ongoing observation and biomarker-driven analyses.

Positioning CLL17 in the Current Treatment Landscape

The results of CLL17 complement and extend findings from earlier studies such as CLL13, CLL14, CAPTIVATE, and GLOW, while providing the first direct, randomized comparison between fixed-duration and continuous targeted therapy. Importantly, the trial was conducted during the emergence of next-generation BTK inhibitors with improved cardiac safety profiles, suggesting that the central question addressed by CLL17, time-limited versus continuous therapy, will remain clinically relevant regardless of the specific BTK inhibitor chosen.

Conclusions

The first analysis of the Phase III CLL17 trial demonstrates that fixed-duration Venetoclax–Obinutuzumab and Venetoclax–Ibrutinib are noninferior to continuous Ibrutinib in previously untreated CLL, with comparable Progression-Free Survival and excellent Overall Survival. These findings provide high-level evidence supporting fixed-duration therapy as a viable frontline strategy for most patients, offering the advantages of treatment-free intervals and deep remissions without compromising efficacy. As follow-up matures, CLL17 will further inform patient selection, remission durability, and the long-term significance of MRD. For now, the trial marks a pivotal step toward more personalized, time-limited treatment strategies in CLL.

Fixed-Duration versus Continuous Treatment for Chronic Lymphocytic Leukemia. Al-Sawaf O, Stumpf J,  Zhang C, et al. for the CLL17 Trial Investigators. Published December 6, 2025. DOI: 10.1056/NEJMoa2515458.

JAYPIRCA® (Pirtobrutinib)

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The FDA on December 3, 2025, granted traditional approval to JAYPIRCA® for adults with relapsed or refractory Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma (CLL/SLL) who have previously been treated with a covalent BTK inhibitor. In 2023, FDA granted accelerated approval to JAYPIRCA® for adults with CLL/SLL who have received at least two prior lines of therapy, including a BTK inhibitor and a BCL-2 inhibitor. JAYPIRCA® is a product of Eli Lilly and Company.

FDA Approves Pirtobrutinib in Relapsed/Refractory CLL/SLL

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SUMMARY: The FDA on December 3, 2025 granted traditional approval to Pirtobrutinib (JAYPIRCA®) for adults with relapsed or refractory Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma (CLL/SLL) who have previously been treated with a covalent BTK inhibitor. In 2023, FDA granted accelerated approval to Pirtobrutinib for adults with CLL/SLL who have received at least two prior lines of therapy, including a BTK inhibitor and a BCL-2 inhibitor.

The American Cancer Society estimates that for 2025, about 23,690 new cases of Chronic Lymphocytic Leukemia (CLL) will be diagnosed in the US and 4460 patients will die of the disease. CLL accounts for about one-quarter of the new cases of leukemia. The average age of patients diagnosed with CLL is around 70 years, and is rarely seen in people under age 40, and is extremely rare in children. Patients with CLL often receive continuous therapy with either Brutons Tyrosine Kinase (BTK) inhibitor, time limited therapy with BCL2 inhibitor Venetoclax given along with anti-CD20 antibody Obinutuzumab, or under certain circumstances, chemoimmunotherapy.

Brutons Tyrosine Kinase (BTK) is a member of the Tec family of kinases, downstream of the B-cell receptor, and is predominantly expressed in B-cells. It is a mediator of B-cell receptor signaling in normal and transformed B-cells. BTK inhibitors inhibit cell proliferation and promote programmed cell death (Apoptosis) by blocking B-cell activation and signaling. BTK is a validated molecular target found across numerous B-cell leukemias and lymphomas including Chronic Lymphocytic Leukemia (CLL), Mantle Cell Lymphoma (MCL), and Waldenstrom Macroglobulinemia (WM).

The 3 covalent BTK inhibitors (cBTKi) presently approved by the FDA for CLL/SLL include Ibrutinib (IMBRUVICA®) Acalabrutinib (CALQUENCE®), and Zanubrutinib (BRUKINSA®). Although covalent BTK inhibitors have dramatically improved outcomes for patients with CLL or SLL, they are not curative. Despite the efficacy of covalent BTK inhibitors, treatment failure often occurs through development of resistance or intolerance.

Pirtobrutinib (JAYPIRCA®) is a next-generation, highly selective, reversible, non-covalent BTK inhibitor (BTKi), developed to reversibly bind BTK, deliver consistently high target coverage regardless of BTK turnover rate, and preserve activity in the presence of the C481 acquired resistance mutations. Pirtobrutinib is 300 times more selective in BTK inhibition versus 98% of other kinases tested in preclinical studies, and inhibits both wild type and C481-mutant BTK with equal low nM potency, and has favorable oral pharmacology. Pirtobrutinib is well tolerated and demonstrated encouraging efficacy and safety in early-phase studies, leading to FDA accelerated approval in December 2023 for patients with CLL/SLL who have received ≥2 prior lines of therapy, including both a BTKi and a BCL-2 inhibitor.

Relapsed/Refractory (R/R) Chronic Lymphocytic Leukemia (CLL) and Small Lymphocytic Lymphoma (SLL) in the post–covalent Bruton Tyrosine Kinase Inhibitor (cBTKi) setting remains a major therapeutic challenge. No prospective, randomized trials have previously evaluated treatment options in this population, and real-world data suggest poor outcomes, particularly after sequential covalent BTKi and BCL-2 inhibitor exposure. The present FDA approval was based on the BRUIN CLL-321 study.

Study Design
BRUIN CLL-321 is the first global, randomized, multicenter, Phase III trial conducted exclusively in patients with R/R CLL/SLL previously treated with a cBTKi.

  • Design: Open-label, 1:1 randomization to Pirtobrutinib 200 mg PO daily (N=119) vs. investigator’s choice (IC) of Idelalisib plus Rituximab (IdelaR-N=82) or Bendamustine plus Rituximab (BR-N=37).
  • Population: 238 patients; median 3 prior therapies; 50% had prior Venetoclax; high prevalence of high-risk genomic features (del[17p]/TP53 mutation ~54%, complex karyotype up to 72%).
  • Endpoints: Primary endpoint was Independent Review Committee (IRC)–assessed Progression-Free Survival (PFS). Secondary endpoints included Time to Next Treatment or death (TTNT), Overall Survival (OS), Overall Response Rate (ORR), and Safety.

Patients could cross over from IC to Pirtobrutinib upon confirmed progression, and treatment beyond IRC-defined progression was permitted if clinical benefit was maintained.

Efficacy Outcomes

  • PFS: Median 14.0 months with Pirtobrutinib vs. 8.7 months with IdelaR/BR (HR = 0.54; P =0.0002), representing a 46% reduction in the risk of progression or death.
  • TTNT: Median 24.0 months with Pirtobrutinib vs. 10.9 months with IC (HR = 0.37), reflecting sustained clinical benefit beyond protocol-defined progression in many patients.
  • OS: No statistically significant difference at final analysis (HR = 1.09), likely influenced by crossover (75.8% of eligible IC patients switched to Pirtobrutinib).
  • Subgroup Benefit: PFS improvement was consistent across key high-risk subgroups, including those with del(17p)/TP53 mutation, complex karyotype, and unmutated IGHV.

Safety Profile
Pirtobrutinib was generally well tolerated:

  • Grade ≥3 adverse events (AEs): 57.7% with Pirtobrutinib vs. 73.4% with IC.
  • Discontinuations due to AEs: 17.2% vs. 34.9%, respectively.
  • Class-related BTKi toxicities (atrial fibrillation, hypertension, major bleeding) were infrequent, with rates comparable to or lower than background incidence in CLL populations.
  • No cases of Richter transformation were reported in the Pirtobrutinib arm, versus three in the IC group.

Clinical Implications
The BRUIN CLL-321 trial establishes Pirtobrutinib as a new standard of care option for patients with CLL/SLL previously treated with cBTKi, offering:

  • Significant PFS improvement in a population with historically poor prognosis.
  • Prolonged TTNT, which may be more reflective of real-world benefit than PFS alone.
  • Favorable safety profile supporting long-term tolerability.

These findings also raise important considerations for sequencing strategies, including potential use of Pirtobrutinib prior to Venetoclax in certain patients, pending further prospective data (e.g., BRUIN-322 trial).

Takeaway for Practice:
For CLL/SLL patients progressing after cBTKi therapy, Pirtobrutinib offers a meaningful advancement, providing durable disease control with a manageable toxicity profile. BRUIN CLL-321 delivers the first randomized evidence supporting treatment in this setting, addressing a long-standing gap in the therapeutic landscape.

Phase III Trial of Pirtobrutinib Versus Idelalisib/Rituximab or Bendamustine/Rituximab in Covalent Bruton Tyrosine Kinase Inhibitor–Pretreated Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (BRUIN CLL-321). Sharman JP, Munir T, Grosicki S, et al. J Clin Oncol. 2025;43:2538-2549

 

 

Maintaining Physician Preference in CLL Care and Its Impact on Outcomes

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Written by: M. Yair Levy, MD
Sponsored by: BeOne Medicines

Chronic lymphocytic leukemia (CLL) is a heterogeneous disease that has seen a remarkable treatment evolution over the past decade. Approximately one-third of CLL patients will not require treatment, with clinical observation remaining the standard for asymptomatic patients.1 For CLL patients requiring treatment, historical regimens have been limited to cytotoxic chemotherapy, administered alone or in combination with anti-CD20 immunotherapy.2 In 2016, two classes of targeted therapies entered the CLL marketplace. Most notably among these are inhibitors of the anti-apoptotic protein B-cell lymphoma 2 (Bcl2), and the B-cell proliferative regulator Bruton’s tyrosine kinase (BTK).2 Introduction of first-generation covalent BTK inhibitors (cBTKis) was followed by second-generation, as well as non-covalent BTKis.2 The rapid expansion of targeted therapies over the last decade has profoundly impacted the clinical management of CLL.

The multitude of therapeutic options in today’s CLL treatment landscape, which often includes several drugs in a single class, provides oncologists the unprecedented opportunity to weigh the entire clinical picture for each patient, and personalize their treatment strategy accordingly. Clinicians leverage decades of medical training to gauge pharmacokinetic and pharmacodynamic differences between therapies, weighing drug-specific efficacy, tolerability and safety for each patient. There is also concurrent influence from reputable medical bodies, such as NCCN guidelines and FDA approved treatments. Most importantly, every CLL patient and their disease are unique. It is imperative to protect physicians’ decision-making freedom to the degree that it permits individualized treatment approaches and the prescription of specific therapies, without undue external influence.

Step therapy is a growing utilization management strategy among health plan Pharmacy Benefit Managers (PBMs) that threatens physician autonomy. As its colloquial name “fail-first” implies, step therapy is a cost-saving approach that requires a patient to have tried, and failed, alternative drug(s), before the PBM will cover the originally prescribed drug.3 Step therapies transfer the onus of decision-making from the treating physician to a commercial entity, robbing the clinician of their ability to personalize care and maximize patient outcomes. This leads to worsening provider burnout, depersonalization, and exacerbates oncology physician shortages. Step therapies also place additional burden on clinical support staff and negatively impact CLL patient outcomes.

PBM-mandated BTKi coverage is a common scenario that exemplifies how step therapy negatively impacts CLL patient outcomes. In my clinical experience, PBMs have required frontline use of the first-generation BTKi ibrutinib. Ibrutinib is an efficacious drug that has revolutionized CLL treatment, but it is poorly tolerated, as compared with 2nd generation BTKis, which directly contributes to decreased treatment compliance and impacts patient outcomes. Ibrutinib also carries the risk of adverse cardiologic events, including atrial arrythmias, ventricular arrhythmias and sudden death.4 As a provider who has lost a patient due to this adverse event, it’s imperative that safety risks of specific drugs are weighed by an experienced clinician on a case-to-case basis. Furthermore, there is an urgent need for step therapy reform that considers clinical data in determining drug coverage. In the case of BTKi coverage, there is clinical evidence demonstrating a lower risk of adverse cardiologic events with use of second-generation BTKi agents.4 As cancer patient advocates, oncologists must continue to push back against step therapies that infringe on patient safety and well-being, and may adversely affect outcomes.

As oncology drugs continue to enter the ever-changing healthcare marketplace, it’s increasingly critical that physicians communicate the importance of preserving autonomy to PBMs and other decision-making parties. There is potential for other drug pricing provisions, such as those included in the 2022 Inflation Reduction Act (IRA),5 to impact CLL patient outcomes in a manner similar to that which is seen with PBM-mediated step therapy. Under the IRA, the government may select certain medications for which it will cap the cost of for Medicare recipients.5 While designed to reduce patient financial burden, provisions of the IRA, such as the ability to target costs of small molecules (like BTKis) years before other drug types, may have harmful effects on oncology treatment.5 This risks physicians being forced to utilize certain medications for which cost setting has been established, similar to step therapy, and has already been shown to disincentivize the development of small molecule drugs since the IRA was enacted.5 Given that CLL primarily affects elderly populations,2 drug pricing provisions affecting Medicare could impact CLL prescribing patterns, and there is precedent to surmise that commercial payers may adopt similar strategies of government-sponsored programs.

In diseases like CLL where therapeutic nuances matter, restricting access to preferred agents can have profound consequences. While the extra hours spent justifying what seems like every clinical decision, completing paperwork, appealing denials, and engaging in peer-to-peer calls may feel like “death by a thousand paper cuts”, oncologists have the responsibility as patient advocates to do no harm. We must continue to advocate for policies that prioritize patient outcomes over cost-driven algorithms, and ensure that clinical decision-making remains in the hands of those best equipped to make it: the treating physicians.

References:

  1. Shadman M. Diagnosis and Treatment of Chronic Lymphocytic Leukemia: A Review. JAMA. 2023;329(11):918-932. doi:10.1001/jama.2023.1946.
  2. Sekeres S, Lamkin EN, Bravo E Jr, Cool A, Taylor J. Resistance Mutations in CLL: Genetic Mechanisms Shaping the Future of Targeted Therapy. Genes (Basel). 2025;16(9):1064. Published 2025 Sep 10. doi:10.3390/genes16091064.
  3. Royce TJ, Schenkel C, Kirkwood K, Levit L, Levit K, Kircher S. Impact of Pharmacy Benefit Managers on Oncology Practices and Patients. JCO Oncol Pract. 2020;16(5):276-284. doi:10.1200/JOP.19.00606.
  4. Moslehi JJ, Furman RR, Tam CS, et al. Cardiovascular events reported in patients with B-cell malignancies treated with zanubrutinib. Blood Adv. 2024;8(10):2478-2490. doi:10.1182/bloodadvances.2023011641.
  5. The Inflation Reduction Act and Medicare Drug Price “Negotiation”. Pharmaceutical Research and Manufacturers of America (PhRMA) website. https://phrma.org/policy-issues/government-price-setting/inflation-reduction-act. Accessed October 1, 2025.

MRD-Guided Ibrutinib-Venetoclax Therapy Shows Durable Survival Benefit in CLL: Results from the Phase 3 FLAIR Trial

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SUMMARY: The American Cancer Society estimates that for 2025, about 23,690 new cases of Chronic Lymphocytic Leukemia (CLL) will be diagnosed in the US and 4460 patients will die of the disease. CLL accounts for about one-quarter of the new cases of leukemia. The average age of patients diagnosed with CLL is around 70 years, and is rarely seen in people under age 40, and is extremely rare in children. Patients with CLL often receive continuous therapy with either Brutons Tyrosine Kinase (BTK) inhibitors, time limited therapy with BCL2 inhibitor Venetoclax (VENCLEXTA®) given along with anti-CD20 antibody Obinutuzumab, or under certain circumstances, chemoimmunotherapy.

BTK inhibitors approved in the US include first-generation irreversible inhibitor Ibrutinib (IMBRUVICA®), second-generation covalent inhibitors Acalabrutinib (CALQUENCE®) and Zanubrutinib (BRUKINSA®), and the third-generation, reversible (non-covalent) inhibitor Pirtobrutinib (JAYPIRCA®).

Continuous BTK inhibition improves outcomes but is associated with resistance and toxicity over time. Given the complementary mechanisms of action, the combination of Ibrutinib and Venetoclax has been evaluated in multiple trials. Notably, fixed-duration combination therapy improved Progression-Free Survival (PFS) and Overall Survival (OS) compared with chemoimmunotherapy in the GLOW and CAPTIVATE studies, while the CLARITY trial demonstrated the feasibility of Measurable Residual Disease (MRD)-guided therapy in relapsed/refractory CLL.

The Phase 3 FLAIR trial expands this investigation in previously untreated CLL patients, testing whether MRD-guided Ibrutinib–Venetoclax can improve long-term outcomes compared with Ibrutinib alone or Fludarabine, Cyclophosphamide and Rituximab combination (FCR).

Trial Design

  • Population: Patients with previously untreated CLL.
  • Randomization (1:1:1):
    • Ibrutinib–Venetoclax (N=260)
    • Ibrutinib monotherapy (N=263)
    • FCR (N=263)
  • Treatment Regimens:
    • FCR: Six 28-day cycles of Fludarabine, Cyclophosphamide, and Rituximab.
    • Ibrutinib monotherapy: 420 mg orally daily, up to 6 years.
    • Ibrutinib–Venetoclax: Eight-week Ibrutinib lead-in followed by Venetoclax ramp-up to 400 mg daily. Treatment duration (2–6 years) was MRD-guided, with discontinuation allowed after sustained MRD negativity.
  • Primary endpoints:
    • Undetectable MRD in bone marrow within 2 years (Ibrutinib–Venetoclax vs single agent Ibrutinib).
    • PFS (Ibrutinib–Venetoclax vs FCR).
  • Secondary endpoints: PFS (Ibrutinib–Venetoclax vs Ibrutinib alone), OS, and safety.

Key Results

With a median follow-up of 62.2 months, the findings strongly favored the Ibrutinib–Venetoclax combination arm:

  • MRD Negativity (Bone Marrow, ≤2 years):
    • 66.2% with Ibrutinib–Venetoclax combination vs 0% with Ibrutinib alone (P<0.001)
    • 48.3% with FCR
  • Progression-Free Survival (5 years):
    • 93.9% (Ibrutinib–Venetoclax) vs 79.0% with Ibrutinib alone and 58.1% with FCR
      • HR for progression or death = 0.29 (Ibrutinib–Venetoclax vs single agent Ibrutinib, P<0.001), and 0.13 (Ibrutinib–Venetoclax vs FCR, P<0.001)
  • Estimated Overall Survival (5 years):
    • 95.9% (Ibrutinib–Venetoclax) vs 90.5% with Ibrutinib alone and 86.5% with FCR
      • HR for death: 0.41 (Ibrutinib–Venetoclax vs Ibrutinib), and 0.26 (Ibrutinib–Venetoclax vs FCR)
  • IGHV Subgroup Analysis:
    • Unmutated IGHV: Strongest OS benefit with Ibrutinib–Venetoclax compared to Ibrutinib alone (HR for death = 0.30), and compared to FCR (HR for death = 0.16). The Ibrutinib alone group and the FCR group had similar results for OS.
    • Mutated IGHV: Overall Survival outcomes were similar between Ibrutinib–Venetoclax and Ibrutinib alone.
  • Treatment Exposure:
    Median duration of Ibrutinib–Venetoclax was 35 months. The percentage of patients with undetectable MRD in peripheral blood at 2 years was 73.1% in the Ibrutinib–Venetoclax group, 0% in the Ibrutinib-alone group, and 60.8% in the FCR group. The median time to the first occurrence of undetectable MRD in peripheral blood was 13.0 months in the Ibrutinib–Venetoclax group, and was 8.9 months in the FCR group.
  • Safety:
    No new safety signals were reported. Atrial fibrillation and hypertension were more frequent in Ibrutinib-containing arms than FCR, but were manageable with cardiovascular risk optimization. Rates of sudden death were low and similar across groups.

Clinical Implications

The FLAIR trial reinforces MRD-guided Ibrutinib–Venetoclax as a highly effective strategy for previously untreated CLL, achieving durable disease control and survival benefits beyond both continuous BTK inhibitor monotherapy and FCR.

Key takeaways for practice:

  • Deep remissions: Two-thirds of patients achieved bone marrow MRD negativity with Ibrutinib–Venetoclax combination, within 2 years, a strong surrogate for long-term disease control.
  • Superior survival: The 5-year PFS and OS rates with Ibrutinib–Venetoclax combination therapy exceed historical outcomes with continuous BTK inhibition or fixed-duration Venetoclax regimens.
  • IGHV status matters: Patients with unmutated IGHV appear to derive the greatest benefit, whereas outcomes are more similar across strategies in mutated IGHV.
  • Individualized therapy feasible: MRD-guided discontinuation allowed many patients to stop treatment early, balancing efficacy with reduced exposure.

While questions remain regarding optimal duration, cost-effectiveness, and the logistics of real-time MRD monitoring, FLAIR provides compelling evidence that tailored combination therapy could redefine first-line management of CLL, particularly for patients with unmutated IGHV.

Measurable Residual Disease–Guided Therapy for Chronic Lymphocytic Leukemia. Munir T,  Girvan S,  Cairns DA, et al. for the UK CLL Trials Group. N Engl J Med 2025;393:1177-1190

Pirtobrutinib in Relapsed/Refractory CLL/SLL after Prior cBTKi: Phase III BRUIN CLL-321 Results

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SUMMARY: The American Cancer Society estimates that for 2025, about 23,690 new cases of Chronic Lymphocytic Leukemia (CLL) will be diagnosed in the US and 4460 patients will die of the disease. CLL accounts for about one-quarter of the new cases of leukemia. The average age of patients diagnosed with CLL is around 70 years, and is rarely seen in people under age 40, and is extremely rare in children. Patients with CLL often receive continuous therapy with either Brutons Tyrosine Kinase (BTK) inhibitor, time limited therapy with BCL2 inhibitor Venetoclax given along with anti-CD20 antibody Obinutuzumab, or under certain circumstances, chemoimmunotherapy.

Brutons Tyrosine Kinase (BTK) is a member of the Tec family of kinases, downstream of the B-cell receptor, and is predominantly expressed in B-cells. It is a mediator of B-cell receptor signaling in normal and transformed B-cells. BTK inhibitors inhibit cell proliferation and promote programmed cell death (Apoptosis) by blocking B-cell activation and signaling. BTK is a validated molecular target found across numerous B-cell leukemias and lymphomas including Chronic Lymphocytic Leukemia (CLL), Mantle Cell Lymphoma (MCL), and Waldenstrom Macroglobulinemia (WM).

The 3 covalent BTK inhibitors (cBTKi) presently approved by the FDA for CLL/SLL include Ibrutinib (IMBRUVICA®) Acalabrutinib (CALQUENCE®), and Zanubrutinib (BRUKINSA®). Although covalent BTK inhibitors have dramatically improved outcomes for patients with CLL or SLL, they are not curative. Despite the efficacy of covalent BTK inhibitors, treatment failure often occurs through development of resistance or intolerance.

Pirtobrutinib (JAYPIRCA®) is a next-generation, highly selective, reversible, non-covalent BTK inhibitor (BTKi), developed to reversibly bind BTK, deliver consistently high target coverage regardless of BTK turnover rate, and preserve activity in the presence of the C481 acquired resistance mutations. Pirtobrutinib is 300 times more selective in BTK inhibition versus 98% of other kinases tested in preclinical studies, and inhibits both wild type and C481-mutant BTK with equal low nM potency, and has favorable oral pharmacology. Pirtobrutinib is well tolerated and demonstrated encouraging efficacy and safety in early-phase studies, leading to FDA accelerated approval in December 2023 for patients with CLL/SLL who have received ≥2 prior lines of therapy, including both a BTKi and a BCL-2 inhibitor.

Relapsed/Refractory (R/R) Chronic Lymphocytic Leukemia (CLL) and Small Lymphocytic Lymphoma (SLL) in the post–covalent Bruton Tyrosine Kinase Inhibitor (cBTKi) setting remains a major therapeutic challenge. No prospective, randomized trials have previously evaluated treatment options in this population, and real-world data suggest poor outcomes, particularly after sequential covalent BTKi and BCL-2 inhibitor exposure.

Study Design
BRUIN CLL-321 is the first global, randomized, multicenter, Phase III trial conducted exclusively in patients with R/R CLL/SLL previously treated with a cBTKi.

  • Design: Open-label, 1:1 randomization to Pirtobrutinib 200 mg PO daily (N=119) vs. investigator’s choice (IC) of Idelalisib plus Rituximab (IdelaR-N=82) or Bendamustine plus Rituximab (BR-N=37).
  • Population: 238 patients; median 3 prior therapies; 50% had prior Venetoclax; high prevalence of high-risk genomic features (del[17p]/TP53 mutation ~54%, complex karyotype up to 72%).
  • Endpoints: Primary endpoint was Independent Review Committee (IRC)–assessed Progression-Free Survival (PFS). Secondary endpoints included Time to Next Treatment or death (TTNT), Overall Survival (OS), Overall Response Rate (ORR), and Safety.

Patients could cross over from IC to Pirtobrutinib upon confirmed progression, and treatment beyond IRC-defined progression was permitted if clinical benefit was maintained.

Efficacy Outcomes

  • PFS: Median 14.0 months with Pirtobrutinib vs. 8.7 months with IdelaR/BR (HR = 0.54; P =0.0002), representing a 46% reduction in the risk of progression or death.
  • TTNT: Median 24.0 months with Pirtobrutinib vs. 10.9 months with IC (HR = 0.37), reflecting sustained clinical benefit beyond protocol-defined progression in many patients.
  • OS: No statistically significant difference at final analysis (HR = 1.09), likely influenced by crossover (75.8% of eligible IC patients switched to Pirtobrutinib).
  • Subgroup Benefit: PFS improvement was consistent across key high-risk subgroups, including those with del(17p)/TP53 mutation, complex karyotype, and unmutated IGHV.

Safety Profile
Pirtobrutinib was generally well tolerated:

  • Grade ≥3 adverse events (AEs): 57.7% with Pirtobrutinib vs. 73.4% with IC.
  • Discontinuations due to AEs: 17.2% vs. 34.9%, respectively.
  • Class-related BTKi toxicities (atrial fibrillation, hypertension, major bleeding) were infrequent, with rates comparable to or lower than background incidence in CLL populations.
  • No cases of Richter transformation were reported in the Pirtobrutinib arm, versus three in the IC group.

Clinical Implications
The BRUIN CLL-321 trial establishes Pirtobrutinib as a new standard of care option for patients with CLL/SLL previously treated with cBTKi, offering:

  • Significant PFS improvement in a population with historically poor prognosis.
  • Prolonged TTNT, which may be more reflective of real-world benefit than PFS alone.
  • Favorable safety profile supporting long-term tolerability.

These findings also raise important considerations for sequencing strategies, including potential use of Pirtobrutinib prior to Venetoclax in certain patients, pending further prospective data (e.g., BRUIN-322 trial).

Takeaway for Practice:
For CLL/SLL patients progressing after cBTKi therapy, Pirtobrutinib offers a meaningful advancement, providing durable disease control with a manageable toxicity profile. BRUIN CLL-321 delivers the first randomized evidence supporting treatment in this setting, addressing a long-standing gap in the therapeutic landscape.

Phase III Trial of Pirtobrutinib Versus Idelalisib/Rituximab or Bendamustine/Rituximab in Covalent Bruton Tyrosine Kinase Inhibitor–Pretreated Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (BRUIN CLL-321). Sharman JP, Munir T, Grosicki S, et al. J Clin Oncol. 2025;43:2538-2549

 

 

Fixed-Duration CALQUENCE® plus VENCLEXTA® for Previously Untreated CLL

RR

SUMMARY: The American Cancer Society estimates that for 2024, about 20,700 new cases of Chronic Lymphocytic Leukemia (CLL) will be diagnosed in the US and 4440 patients will die of the disease. CLL accounts for about one-quarter of the new cases of leukemia. The average age of patients diagnosed with CLL is around 70 years, and CLL is rarely seen in people under age 40, and is extremely rare in children. Patients with CLL often receive continuous therapy with either Brutons Tyrosine Kinase (BTK) inhibitor, time limited therapy with BCL2 inhibitor Venetoclax given along with anti-CD20 antibody Obinutuzumab, or under certain circumstances, chemoimmunotherapy.

Brutons Tyrosine Kinase (BTK) is a member of the Tec family of kinases, downstream of the B-cell receptor, and is predominantly expressed in B-cells. It is a mediator of B-cell receptor signaling in normal and transformed B-cells. BTK inhibitors inhibit cell proliferation and promote programmed cell death (Apoptosis) by blocking B-cell activation and signaling. BTK is a validated molecular target found across numerous B-cell leukemias and lymphomas including CLL, Mantle Cell Lymphoma (MCL), and Waldenstrom Macroglobulinemia (WM). Four BTK inhibitors are presently approved by the FDA. They include first generation Ibrutinib (IMBRUVICA®) and second generation agents such as Acalabrutinib (CALQUENCE®), Zanubrutinib (BRUKINSA®) and non-covalent BTKi, Pirtobrutinib (JAYPIRCA®).

The pro-survival (anti-apoptotic) protein BCL2 is over expressed by CLL cells and regulates clonal selection and cell survival. Venetoclax (VENCLEXTA®) is a second generation, oral, selective, small molecule inhibitor of BCL2 and restores the apoptotic processes in tumor cells. Venetoclax is frequently combined with the infusion-based drug Obinutuzumab (GAZYVA®), which can impose a logistical burden on patients. The combination of Acalabrutinib plus Venetoclax, were noted to be synergistic.

The AMPLIFY trial is a randomized, global, multi-center, open-label Phase III study designed to assess the efficacy and safety of Acalabrutinib in combination with Venetoclax, with or without Obinutuzumab, compared to investigators choice of standard chemoimmunotherapy. In this study, 867 patients (N=867) across 171 locations worldwide with previously untreated CLL were randomized 1:1:1 to receive a fixed-duration regimen of Acalabrutinib and Venetoclax with Obinutuzumab (AVO; N=286), Acalabrutinib and Venetoclax without Obinutuzumab (AV; N=291), or Standard-of-Care chemoimmunotherapy with either Fludarabine plus Cyclophosphamide and Rituximab (FCR) or Bendamustine plus Rituximab (BR) (FCR/BR; N=290). The median patient age was 61 years, 64.5% were male, and 58.6% had CLL with unmutated IGHV. Eligible patients had an ECOG performance status of 0 to 2 and active disease, requiring treatment as per the International Workshop on CLL 2018 criteria. Patients with prior CLL-specific treatments, 17p deletions, TP53 mutations, transformation of CLL to aggressive Non-Hodgkin Lymphoma, Central Nervous System involvement, or a history of Progressive Multifocal Leukoencephalopathy were excluded. The Primary endpoint of the trial was Progression Free Survival (PFS) as assessed by an Independent Review Committee (IRC). Key Secondary endpoints included PFS assessed by investigators, undetectable Minimal Residual Disease (uMRD; 10-4 cutoff) rate assessed in peripheral blood in the treatment groups, Overall Survival (OS), Overall Response Rate (ORR), Duration of Response, and Time to next treatment.

At a median follow-up of 41 months, both AVO and AV provided a statistically significant improvement in BICR-assessed PFS over the chemoimmunotherapy control arm (HR for AVO was 0.42, and for AV was 0.65, versus FCR/BR; P<0.0001 and P=0.0038, respectively). Approximately 83% of patients in the AVO group remained progression-free at 36 months, compared to 76.8% of patients in the AV group and 66.5% in the FCR/BR group. Median PFS was not reached in the AVO and AV groups, but was 47.6 months in the FCR/BR group. The BICR-assessed Overall Response Rates (ORR) were 92.7% in the AVO group, 92.8% in the AV group, and 75.2% in the FCR/BR group (P<0.0001 for both comparisons). AV demonstrated an OS benefit trend over FCR/BR (HR=0.33; P<0.0001). Serious Adverse Events occurred in 38.4% (AVO group), 24.7% of patients (AV group), and 27.4% (FCR/BR group). Grade 3 or more neutropenia among the treatment groups, was noted in 35.2%, 26.8% and 32.4%, respectively. COVID-19-related deaths affected 25 patients in the AVO group, 10 patients in the AV group, and 21 patients in the FCR/BR group.

In conclusion, the AMPLIFY study successfully met its Primary endpoint, demonstrating superior PFS with AVO and AV compared to standard chemoimmunotherapy. These combinations offer deep and durable responses, paving the way for an easier, more effective treatment option. AV offers the first all-oral fixed-duration regimen for fit treatment naive CLL patients, providing significant convenience and manageable safety profiles. The addition of Obinutuzumab (AVO) improved efficacy but was associated with higher rates of serious adverse events and COVID-19-related deaths.

Fixed-Duration Acalabrutinib Plus Venetoclax with or without Obinutuzumab Versus Chemoimmunotherapy for First-Line Treatment of Chronic Lymphocytic Leukemia: Interim Analysis of the Multicenter, Open-Label, Randomized, Phase 3 AMPLIFY Trial. Abstract#1009. Brown JR, SeymourJF, Jurczak W, et al. Presented at ASH Annual Meeting and Exposition 2024.